This proposal represents a continuation of the past 27 years of research into the mechanisms of ventilation perfusion ratio distribution in the lungs. In the past years, we have addressed the mechanisms affecting VA/Q heterogeneity using the multiple inert gas elimination technique (MIGET), a tool for quantitatively assessing pulmonary gas exchange. MIGET yields global information about VA/Q distribution without providing specific information regarding either Q or VA distributions. The proposed research will take advantage of our past work coupled with the recent development of the use of fluorescent microspheres to assess regional distribution of perfusion to small 1.9 cm3 volumes of the lung and the phase IIi slope ratio analysis of N2 washout to assess mechanisms of ventilation distribution. These methods allow resolution of blood flow within small regions of the lung and separation of ventilation inhomogeneity into its central (airway) and peripheral (acinar) components. We use these methods to separate the relative importance of several factors (lung blood flow, lung blood flow, lung volume, alveolar PO2, alveolar PCO2, gravity and exercise) in determining VA/Q heterogeneity. Most of our experiments will focus on the dog (with a reduced hypoxic pulmonary vasoconstriction (HPV) and increased collateral ventilation) and the pig (increased Hpv and no collateral ventilation). These animals will be studied at different levels of resolution; the whole animal, the separated lung preparation and the isolated lobule preparation. In order to study unanesthetized animals, the thoroughbred horse will be studied as a model for evaluating high cardiac output states and large vertical lung size. We will also use the centrifuged (high-gravity) unanesthetized pig model to evaluate the role of gravity and positive pressure breathing on lung function.